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Objective: Knee osteoarthritis (OA) is a leading cause of chronic pain in adults and shows wide interindividual variability, with peripheral and central factors contributing to the pain experience. Periarticular factors, such as muscle quality (eg, echo intensity [EI] and shear wave velocity [SWV]), may contribute to knee OA pain; however, the role of muscle quality in OA symptoms has yet to be fully established., Methods: Twenty-six adults (age >50 years) meeting clinical criteria for knee OA were included in this cross-sectional study. Quantitative ultrasound imaging was used to quantify EI and SWV in the rectus femoris of the index leg. Pearson correlations followed by multiple linear regression was used to determine associations between muscle quality and pain, controlling for strength, age, sex, and body mass index., Results: EI and SWV were significantly associated with movement-evoked pain (b = 0.452-0.839, P = 0.024-0.029). Clinical pain intensity was significantly associated with SWV (b = 0.45, P = 0.034), as were pressure pain thresholds at the medial (b = -0.41, P = 0.025) and lateral (b = -0.54, P = 0.009) index knee joint line, adjusting for all covariates. Pain interference was significantly associated with knee extension strength (b = -0.51, P = 0.041)., Conclusion: These preliminary findings suggest that EI and SWV may impact knee OA pain and could serve as malleable treatment targets. Findings also demonstrate that muscle quality is a unique construct, distinct from muscle strength, which may impact pain and treatment outcomes. More research is needed to fully understand the role of muscle quality in knee OA., (© 2024 American College of Rheumatology.)

Osteoarthritis (OA) manifests with chronic pain, motor impairment, and proprioceptive changes. However, the role of the brain in the disease is largely unknown. Here, we studied brain networks using the mathematical properties of graphs in a large sample of knee and hip OA (KOA, n = 91; HOA, n = 23) patients. We used a robust validation strategy by subdividing the KOA data into discovery and testing groups and tested the generalizability of our findings in HOA. Despite brain global topological properties being conserved in OA, we show there is a network wide pattern of reorganization that can be captured at the subject-level by a single measure, the hub disruption index. We localized reorganization patterns and uncovered a shift in the hierarchy of network hubs in OA: primary sensory and motor regions and parahippocampal gyrus behave as hubs and insular cortex loses its central placement. At an intermediate level of network structure, frontoparietal and cingulo-opercular modules showed preferential reorganization. We examined the association between network properties and clinical correlates: global disruption indices and isolated degree properties did not reflect clinical parameters; however, by modeling whole brain nodal degree properties, we identified a distributed set of regions that reliably predicted pain intensity in KOA and generalized to hip OA. Together, our findings reveal that while conserving global topological properties, brain network architecture reorganizes in OA, at both global and local scale. Network connectivity related to OA pain intensity is dissociated from the major hub disruptions, challenging the extent of dependence of OA pain on nociceptive signaling., (© 2020 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Objective: To assess the relationship between patients' expectations for total knee arthroplasty (TKA) and satisfaction with surgical outcome., Methods: This prospective cohort study recruited patients with knee osteoarthritis (OA) ages ≥30 years who were referred for TKA at 2 hip/knee surgery centers in Alberta, Canada. Those who received primary, unilateral TKA completed questionnaires pre-TKA to assess TKA expectations (17-item Hospital for Special Surgery [HSS] TKA Expectations questionnaire) and contextual factors (age, sex, Western Ontario and McMaster Universities Osteoarthritis Index pain score, Knee Injury and Osteoarthritis Outcome Score physical function short form [KOOS-PS], 8-item Patient Health Questionnaire depression scale, body mass index [BMI], comorbidities, and prior joint replacement), and 1-year post-TKA to assess overall satisfaction with TKA results. Using multivariate logistic regression, we examined the relationship between TKA expectations (HSS TKA outcomes considered to be very important) and postoperative satisfaction (very satisfied versus somewhat satisfied versus dissatisfied). Adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated., Results: At 1 year, 1,266 patients with TKA (92.1%) reported their TKA satisfaction (mean ± SD age 67.2 ± 8.8 years, 60.9% women, and mean BMI 32.6 kg/m 2 ); 74.7% of patients were very satisfied, 17.1% were somewhat satisfied, and 8.2% were dissatisfied. Controlling for other factors, an expectation of TKA to improve patients' ability to kneel was associated with lower odds of satisfaction (adjusted OR 0.725 [95% CI 0.54-0.98]). An expectation of TKA to improve psychological well-being was associated with lower odds of satisfaction for individuals in the lowest tertile of pre-TKA KOOS-PS scores (adjusted OR 0.49 [95% CI 0.28-0.84]), but higher odds for those in the highest tertile (adjusted OR 2.37 [95% CI 1.33-4.21])., Conclusion: In patients with TKA, preoperative expectations regarding kneeling and psychological well-being were significantly associated with the level of TKA satisfaction at 1 year. Ensuring that patients' expectations are achievable may enhance appropriate provision of TKA., (© 2020, American College of Rheumatology.)

Rheumatoid arthritis (RA) is currently diagnosed and treated when an individual presents with signs and symptoms of inflammatory arthritis (IA) as well as other features, such as autoantibodies and/or imaging findings, that provide sufficient confidence that the individual has RA-like IA (e.g., meeting established classification criteria) that warrants therapeutic intervention. However, it is now known that there is a stage of seropositive RA during which circulating biomarkers and other factors (e.g., joint symptoms) can be used to predict if and when an individual who does not currently have IA may develop future clinically apparent IA and classifiable RA. Indeed, the discovery of the "pre-RA" stage of seropositive disease has led to the development of several clinical trials in which individuals are studied to identify ways to delay or prevent the onset of clinically apparent IA/RA. This review focuses on several issues pertinent to understanding the prevention of RA. These include discussion of the pathogenesis of pre-RA development, prediction of the likelihood and timing of future classifiable RA, and a review of completed and ongoing clinical trials in RA prevention. Furthermore, this review discusses challenges and opportunities to be addressed to effect a paradigm shift in RA, where in the near future, proactive risk assessment focused on prevention of RA will become a public health strategy in much the same manner as cardiovascular disease is managed today., (© 2020, American College of Rheumatology.)

Objective: Pain sensitization contributes to the complex osteoarthritis (OA) pain experience. The relationship between imaging features of hand OA and clinically assessed pain sensitization is largely unexplored. This study was undertaken to examine the association of structural and inflammatory features of hand OA with local pressure pain thresholds (PPTs) in the Nor-Hand study., Methods: The cross-sectional relationship of severity of structural radiographic features of hand OA (measured according to the Kellgren/Lawrence scale [grade 0-4] and the absence or presence of erosive joint disease) as well as ultrasound-detected hand joint inflammation (assessed by gray-scale synovitis [grade 0-3] and the absence or presence of power Doppler activity) to the PPTs of 2 finger joints was examined by multilevel regression analyses adjusted for age, sex, and body mass index, using beta values with 95% confidence intervals (95% CIs)., Results: A total of 570 joints in 285 participants included in the Nor-Hand study were assessed. Greater structural and inflammatory severity was associated with lower PPTs, with adjusted beta values of -0.5 (95% CI -0.6, -0.4) per Kellgren/Lawrence grade increase, -1.4 (95% CI -1.8, -0.9) for erosive versus non-erosive joints, -0.7 (95% CI -0.9, -0.6) per gray-scale synovitis grade increase, and -1.5 (95% CI -1.8, -1.1) for joints with power Doppler activity on ultrasound versus those without., Conclusion: Greater severity of structural pathologic features and hand joint inflammation was associated with lower PPTs in the finger joints of patients with hand OA, indicating pain sensitization. Our results indicate that pain sensitization might be driven by structural and inflammatory pathology in hand OA., (© 2020 The Authors. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.)

Objective: Massive weight loss leads to marked knee pain reduction in individuals with knee pain, but the reason for the reduction in pain is unknown. This study was undertaken to quantify the contribution of magnetic resonance imaging (MRI)-evidenced changes in pain-sensitive structures, bone marrow lesions (BMLs), and synovitis, and changes in pain sensitization or depressive symptoms, to knee pain improvement after substantial weight loss., Methods: Morbidly obese patients with knee pain on most days were evaluated before bariatric surgery or medical weight management and at 1-year follow-up for BMLs and synovitis seen on MRI, the pressure pain threshold (PPT) at the patella and the right wrist, depressive symptoms (using the Center for Epidemiologic Studies Depression scale [CES-D]), and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain survey. Natural-effects models were used to quantify the extent that achieving a minimum clinically important difference (MCID) of ≥18% on the WOMAC pain scale could be mediated by weight loss-induced changes in BMLs, synovitis, PPT, and depressive symptoms., Results: Of 75 participants, 53.3% lost ≥20% of weight by 1 year. Of these, 75% attained the MCID for pain improvement, compared with 34.3% in those who had <20% weight loss. Mediation analyses suggested that, in those with at least 20% weight loss, the odds of pain improvement increased by 62%, 15%, and 22% through changes in patella PPT, wrist PPT, and CES-D, respectively, but pain improvement was not mediated by MRI changes in BMLs or synovitis., Conclusion: Weight loss-induced knee pain improvement is partially mediated by changes in pain sensitization and depressive symptoms but is independent of MRI changes in BMLs and synovitis., (© 2019, American College of Rheumatology.)

Background: Conditioned pain modulation (CPM) and offset analgesia are different features of descending pain inhibition. This study investigated CPM, offset analgesia and clinical pain measures in patients with knee osteoarthritis (KOA) before and after treatment with the combination of a non-steroidal anti-inflammatory drug (NSAIDs) plus acetaminophen., Methods: Forty-two patients with KOA received Ibuprofen 1.2 g/daily and acetaminophen 3.0 g/daily for three weeks. Before administration, CPM magnitude was assessed as the difference between cuff pain detection (cPDT) with and without a conditioning stimulus (evoked by tourniquet pain). Offset analgesia was assessed as the pain intensities evoked by a constant 46°C for 30-s stimulus compared to an offset analgesia paradigm of 46°C for 5-s, 47°C for 5-s and 46°C for 20-s. The worst pain within the last 24-hr and pain during activity were assessed before and after treatment., Results: Clinical pain significantly decreased after treatment (p < 0.001) and less efficient CPM before treatment was associated with weaker analgesic effect (R = 0.354, p = 0.043). No significant modulation of CPM or offset analgesia was found for the treatment., Conclusion: This study found that less efficient CPM is associated with reduced analgesic effect of NSAIDs plus acetaminophen in patients with KOA whereas the treatment did not modulate CPM nor offset analgesia magnitude., Significance: This study demonstrated that conditioned pain modulation is correlated with the response to a standard pharmaceutical interventions treating osteoarthritis pain. Furthermore, we demonstrated that a decrease in clinical pain intensity is not associated with a normalization of conditioned pain modulation or offset analgesia, which questions if restoring these descending pain inhibitory mechanisms are pain intensity driven., (© 2019 European Pain Federation - EFIC®.)

Objective: To prospectively assess the efficacy, general safety, and joint safety of fasinumab, an anti-nerve growth factor monoclonal antibody, in osteoarthritis (OA) hip and/or knee pain., Methods: Patients with moderate-to-severe OA pain (knee or hip) and history of inadequate response or intolerance to analgesics were randomized to receive fasinumab (at 1 mg, 3 mg, 6 mg, or 9 mg) or placebo every 4 weeks over 16 weeks and were followed up to week 36. Efficacy end points were the change from baseline to week 16 in the pain and physical function subscale scores of the Western Ontario and McMaster Universities OA Index (WOMAC), and patient global assessment (PGA) of OA. Joints were monitored at scheduled assessments (by plain film radiography and magnetic resonance imaging) during treatment and follow-up, and if prompted, at the time of active joint symptoms., Results: Of the 421 patients randomized, 342 completed the 36-week study. All doses of fasinumab yielded statistically significant and clinically important reductions in pain compared to placebo (least squares mean difference in WOMAC pain subscale scores at week 16 ranging -0.78 to -1.40), without any clear dose dependence. Physical function and PGA scores improved in parallel. Treatment-emergent adverse event rates were 17% with fasinumab and 10% with placebo, and 4% and 1% of patients, respectively, discontinued treatment. Arthropathies (25 in total, 7% of fasinumab-treated patients and 1% of placebo-treated patients) occurred in a dose-dependent manner, with 2 occurring in patients receiving the lowest dose of fasinumab and 10 in patients receiving the highest dose. Most of the arthropathies (16 of 25) were discovered with scheduled radiographs and not based on symptoms. Destructive arthropathy (in 1 of 337 treated patients) occurred in 1 patient who was receiving 6 mg fasimumab., Conclusion: Fasinumab provided improvements in OA pain and function, even in those benefitting little from previous analgesics. The observed benefit-to-risk relationship favors further clinical development to explore the lowest doses of fasinumab in patients with knee or hip OA., (© 2019 Regeneron Pharmaceuticals, Inc. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.)

Objective: Mechanisms responsible for osteoarthritic (OA) pain remain poorly understood, and current analgesic therapies are often insufficient. This study was undertaken to characterize and pharmacologically test the pain phenotype of a noninvasive mechanical joint loading model of OA, thus providing an alternative murine model for OA pain., Methods: The right knees of 12-week-old male C57BL/6 mice were loaded at 9N or 11N (40 cycles, 3 times per week for 2 weeks). Behavioral measurements of limb disuse and mechanical and thermal hypersensitivity were acquired before mechanical joint loading and monitored for 6 weeks postloading. The severity of articular cartilage lesions was determined postmortem with the Osteoarthritis Research Society International scoring system. To assess efficacy of various treatments for pain, 9N-loaded mice were treated for 4 weeks with diclofenac (10 mg/kg), gabapentin (100 mg/kg), or anti-nerve growth factor (anti-NGF) (3 mg/kg)., Results: Mechanical hypersensitivity and weight bearing worsened significantly in 9N-loaded mice (n = 8) and 11N-loaded mice (n = 8) 2 weeks postloading, compared to baseline values and nonloaded controls. Maximum OA scores of ipsilateral knees confirmed increased cartilage lesions in 9N-loaded mice (mean ± SEM 2.8 ± 0.2; P < 0.001) and 11N-loaded mice (5.3 ± 0.3; P < 0.001), compared to nonloaded controls (1.0 ± 0.0). Gabapentin and diclofenac restored pain behaviors to baseline values after 2 weeks of daily treatment, and gabapentin was more effective than diclofenac. A single injection of anti-NGF alleviated nociception 2 days after treatment and remained effective for 2 weeks, with a second dose inducing stronger and more prolonged analgesia., Conclusion: Our findings show that mechanical joint loading induces OA lesions in mice and a robust pain phenotype that can be reversed using analgesics known to alleviate OA pain in patients. This establishes the use of mechanical joint loading as an alternative model for the study of OA pain., (© 2019 The Authors. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.)

The study aims to evaluate whether bone scintigraphy is effective in diagnosing temporomandibular joint (TMJ) osteoarthritis (OA) in juvenile patients. A retrospective study was conducted with 356 consecutive patients with TMJ-OA who were clinically assessed according to the Research Diagnostic Criteria for Temporomandibular Disorders. Patients were assigned to three groups based on their ages: Group 1: aged 12-16 years; Group 2: aged 17-19 years; and Group 3: aged 20 years. Additionally, we performed qualitative and quantitative analyses of bone scintigraphy images for the TMJ uptake ratio of the involved joint. The diagnostic rate of TMJ-OA ( n  = 356, 100%), and the overall presence of subjective pain ( n  = 282, 77.3%) was closest to the results of bone scintigraphy ( n = 333, 91.2%). In addition, reported TMJ pain was significantly associated only with the results of bone scintigraphy and not with the results of panoramic radiography or cone beam computed tomography (CBCT) in all age groups. With CBCT as the reference standard, the optimal cutoff values of the uptake ratio for the diagnosis of TMJ-OA were 2.171 and 2.017 in Groups 1 and 2, respectively ( P value < 0.05). Our results suggest that bone scintigraphy can be considered a useful modality for diagnosing TMJ-OA in juvenile patients., Competing Interests: The authors declare no conflicts of interest.

Background: Chronic pain conditions, especially osteoarthritis (OA), are as common in individuals with Alzheimer's disease (AD) as in the general elderly population, which results in detrimental impact on patient's quality of life. However, alteration in perception of pain in AD coupled with deteriorating ability to communicate pain sensations often result in under-diagnosis and inappropriate management of pain. Therefore, a better understanding of mechanisms in chronic pain processing in AD is needed. Here, we explored the development and progression of OA pain and the effect of analgesics in a transgenic mouse model of AD., Methods: Unilateral OA pain was induced chemically, via an intra-articular injection of monosodium iodoacetate (MIA) in the left knee joint of AD-mice (TASTPM) and age- and gender-matched C57BL/6J (WT). Pharmacological and biochemical assessments were conducted in plasma and spinal cord tissue., Results: MIA resulted in hind paw mechanical hypersensitivity (allodynia), initiating on day 3, in TASTPM and WT controls. However, from 14 to 28 days, TASTPM displayed partial attenuation of allodynia and diminished spinal microglial response compared to WT controls. Naloxone, an opioid antagonist, re-established allodynia levels as observed in the WT group. Morphine, an opioid agonist, induced heightened analgesia in AD-mice whilst gabapentin was devoid of efficacy. TASTPM exhibited elevated plasma level of β-endorphin post-MIA which correlated with impaired allodynia., Conclusions: These results indicate an alteration of the opioidergic system in TASTPM as possible mechanisms underlying impaired persistent pain sensitivity in AD. This work provides basis for re-evaluation of opioid analgesic use for management of pain in AD., Significance: This study shows attenuated pain-like behaviour in a transgenic mouse model of Alzheimer's disease due to alterations in the opioidergic system and central plasticity mechanisms of persistent pain., (© 2018 The Authors. European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation -EFIC ®.)

Background: Accumulating evidence indicates that knee pain gives rise to sensory and motor alterations, however, whether different profile of knee pain causes different alterations has not been investigated. The purpose of this experimental study is to clarify characteristics of medial and lateral knee pain and its potential for modulating sensory and motor function in humans., Methods: Fourteen healthy men were included. Medial knee pain (MP) was induced by injection of hypertonic saline (0.5 mL) into the tibial insertion of the medial collateral ligament. For comparison, lateral knee pain (LP) was induced by injection of hypertonic saline identically into the iliotibial tract. Isotonic saline was injected contralaterally as control. Pain intensity was assessed on a continuous electronic visual analogue scale (VAS). Before, during and after the painful state, pressure pain thresholds from the knee (PPTs), maximal isometric muscle strength of the quadriceps and grip power were assessed bilaterally., Results: MP demonstrated significantly higher VAS scores than LP and compared with control. PPTs decreased on medial and lateral knee in MP but only on the lateral knee in LP. Quadriceps muscle strength and grip power reduced bilaterally in both models, however, MP caused significantly greater reduction of ipsilateral quadriceps strength compared with LP., Conclusion: Medial knee pain has a greater impact on deep tissue hyperalgesia and reduction of the muscle strength compared with lateral knee pain. This is a novel finding that should be taken into consideration in a treatment strategy for painful knee patients., Significance: The experimental medial knee pain model demonstrated higher pain intensity, more localized pain distribution, widespread deep tissue hyperalgesia and more severe inhibition of muscle strength compared with the lateral knee pain model., (© 2018 European Pain Federation - EFIC®.)

Background: Preoperative progressive resistance training (PRT) is controversial in patients scheduled for total knee arthroplasty (TKA), because of the concern that it may exacerbate knee joint pain and effusion., Objective: To examine whether preoperative PRT initiated 5 weeks prior to TKA would exacerbate pain and knee effusion, and would allow a progressively increased training load throughout the training period that would subsequently increase muscle strength., Design: Secondary analyses from a randomized controlled trial (NCT01647243)., Setting: University Hospital and a Regional Hospital., Patients: A total of 30 patients who were scheduled for TKA due to osteoarthritis and assigned as the intervention group., Methods: Patients underwent unilateral PRT (3 sessions per week). Exercise loading was 12 repetitions maximum (RM) with progression toward 8 RM. The training program consisted of 6 exercises performed unilaterally., Main Outcome Measures: Before and after each training session, knee joint pain was rated on an 11-point scale, effusion was assessed by measuring the knee joint circumference, and training load was recorded. The first and last training sessions were initiated by 1 RM testing of unilateral leg press, unilateral knee extension, and unilateral knee flexion., Results: The median pain change score from before to after each training session was 0 at all training sessions. The average increase in knee joint effusion across the 12 training sessions was a mean 0.16 cm ± 0.23 cm. No consistent increase in knee joint effusion after training sessions during the training period was found (P = .21). Training load generally increased, and maximal muscle strength improved as follows: unilateral leg press: 18% ± 30% (P = .03); unilateral knee extension: 81% ± 156% (P < .001); and unilateral knee flexion: 53% ± 57% (P < .001)., Conclusion: PRT of the affected leg initiated shortly before TKA does not exacerbate knee joint pain and effusion, despite a substantial progression in loading and increased muscle strength. Concerns for side effects such as pain and effusion after PRT seem unfounded., Level of Evidence: I., (Copyright © 2018. Published by Elsevier Inc.)

Background: Few studies have investigated the associations between patient-reported outcome and gait in patients with anterior cruciate ligament (ACL) injury and reconstruction over time. Because there is an association between ACL rupture and the presence of osteoarthritis later in life, a better understanding of these relationships will help to elucidate how patients' gait pattern may affect pain and symptoms, potentially leading to better treatment for or preventing the development of knee OA., Objective: To evaluate the associations between gait characteristics and self-reported pain and symptoms before, 6 months after, and 1 year after anterior cruciate ligament reconstruction., Design: Prospective cohort study., Setting: The Human Performance Center at the Orthopedic Institute at the University of California, San Francisco., Patients: Patients with full unilateral ACL tears were enrolled. A total of 43 patients were included at 12 months postsurgery., Methods: The independent variable in this study comprised specific gait variables in patients who had undergone ACL reconstruction. At each time point, 3-dimensional motion analysis was performed. Participants also completed the Knee Osteoarthritis Outcome Score (KOOS) questionnaire., Main Outcomes Measurements: The primary study outcome measurement was the KOOS and was planned before data collection began. Partial correlations were used to examine cross-sectional associations between gait characteristics and KOOS pain and symptom scores at all time points. In addition, partial correlations were performed to examine the associations between change in postoperative KOOS from 6 months to 1 year and gait characteristics at baseline and 6 months., Results: Significant associations between KOOS and gait characteristics were found at all time points, including an association between peak medial ground reaction force and pain (r = -0.344, P = .02) and symptoms (r = -0.407, P = .007) at baseline., Conclusions: Specific gait variables may be predictive of greater pain and symptoms and less improvement over time postreconstruction. This could help to inform rehabilitation exercises post injury and pre reconstruction., Level of Evidence: IV., (Copyright © 2018 American Academy of Physical Medicine and Rehabilitation. Published by Elsevier Inc. All rights reserved.)

Background: Substance P (SP) is a pain- and inflammation-related neuropeptide which preferentially binds to the neurokinin receptor 1 (NK 1 ). SP and NK 1 receptors have been implicated in joint pain, inflammation and damage in animal models and human studies of osteoarthritis (OA). The aim of this study was to test if genetic variation at the neurokinin 1 receptor gene (TACR1) is associated with pain in individuals with radiographic knee OA., Methods: Participants from the Genetics of OA and Lifestyle study were used for the discovery group (n = 1615). Genotype data for six SNPs selected to cover most variation in the TACR1 gene were used to test for an association with symptomatic OA. Replication analysis was performed using data from the Chingford 1000 Women Study, Hertfordshire Cohort Study, Tasmanian Older Adult Cohort Study and the Clearwater OA Study. In total, n = 1715 symptomatic OA and n = 735 asymptomatic OA individuals were analysed., Results: Out of six SNPs tested in the TACR1 gene, one (rs11688000) showed a nominally significant association with a decreased risk of symptomatic OA in the discovery cohort. This was then replicated in four additional cohorts. After adjusting for age, gender, body mass index and radiographic severity, the G (minor) allele at rs11688000 was associated with a decreased risk of symptomatic OA compared to asymptomatic OA cases (p = 9.90 × 10 -4 , OR = 0.79 95% 0.68-0.90 after meta-analysis)., Conclusions: This study supports a contribution from the TACR1 gene in human OA pain, supporting further investigation of this gene's function in OA., Significance: This study contributes to the knowledge of the genetics of painful osteoarthritis, a condition which affects millions of individuals worldwide. Specifically, a contribution from the TACR1 gene to modulating pain sensitivity in osteoarthritis is suggested., (© 2017 European Pain Federation - EFIC®.)

Objective: Exercise is commonly recommended for patients with osteoarthritis (OA) pain. However, whether exercise is beneficial in ameliorating ongoing pain that is persistent, resistant to nonsteroidal antiinflammatory drugs (NSAIDs), and associated with advanced OA is unknown., Methods: Rats treated with intraarticular (IA) monosodium iodoacetate (MIA) or saline underwent treadmill exercise or remained sedentary starting 10 days postinjection. Tactile sensory thresholds and weight bearing were assessed, followed by radiography at weekly intervals. After 4 weeks of exercise, ongoing pain was assessed using conditioned place preference (CPP) to IA or rostral ventromedial medulla (RVM)-administered lidocaine. The possible role of endogenous opioids in exercise-induced pain relief was examined by systemic administration of naloxone. Knee joints were collected for micro-computed tomography (micro-CT) analysis to examine pathologic changes to subchondral bone and metaphysis of the tibia., Results: Treadmill exercise for 4 weeks reversed MIA-induced tactile hypersensitivity and weight asymmetry. Both IA and RVM lidocaine D35, administered post-MIA, induced CPP in sedentary but not exercised MIA-treated rats, indicating that exercise blocks MIA-induced ongoing pain. Naloxone reestablished weight asymmetry in MIA-treated rats undergoing exercise and induced conditioned place aversion, indicating that exercise-induced pain relief is dependent on endogenous opioids. Exercise did not alter radiographic evidence of OA. However, micro-CT analysis indicated that exercise did not block lateral subchondral bone loss or trabecular bone loss in the metaphysis, but did block MIA-induced medial bone loss., Conclusion: These findings support the conclusion that exercise induces pain relief in advanced, NSAID-resistant OA, likely through increased endogenous opioid signaling. In addition, treadmill exercise blocked MIA-induced bone loss in this model, indicating a potential bone-stabilizing effect of exercise on the OA joint., (© 2017, American College of Rheumatology.)

Objective: To determine the ability of drugs that activate inhibitory G protein-coupled receptors (GPCRs) expressed in peripheral voltage-gated sodium channel 1.8 (Na V 1.8)-positive sensory neurons to control osteoarthritis (OA)-associated pain., Methods: We used designer receptors exclusively activated by a designer drug (DREADD) technology, which employs engineered GPCRs to activate or inhibit neurons upon binding the synthetic ligand clozapine N-oxide (CNO). Na V 1.8-Pdi C57BL/6 mice were generated to express the inhibitory DREADD receptor Pdi in Na V 1.8-expressing sensory neurons. Destabilization of the medial meniscus (DMM) surgery was performed in 10-week-old male mice. Four, 8, 12, or 16 weeks after surgery, knee hyperalgesia or hind paw mechanical allodynia was tested. Subsequently, CNO or vehicle was administered, and the effect on pain-related behaviors was measured by a blinded observer. Morphine was used as a control., Results: Immunohistochemistry and electrophysiology confirmed functional expression of the inhibitory DREADD receptor Pdi by Na V 1.8-positive sensory neurons. Acute inhibition of Na V 1.8-expressing neurons in mice treated with CNO reduced knee hyperalgesia 4 weeks after DMM surgery and reduced mechanical allodynia 8 weeks after DMM surgery. Inhibition had no effect on pain-related behaviors 12 and 16 weeks after DMM surgery. Morphine, a drug that activates GPCRs in the peripheral and central nervous systems, was still effective in the later stage of experimental OA., Conclusion: Chemogenetic inhibition of Na V 1.8-expressing neurons blocks knee hyperalgesia and mechanical allodynia in early experimental OA, but is no longer efficacious in the later stages. These data indicate that activation of inhibitory GPCRs located solely outside the central nervous system may be ineffective in treating chronic OA pain., (© 2017, American College of Rheumatology.)

Objective: Relapsing polychondritis (RP) is a rare condition characterized by recurrent inflammation of cartilaginous tissue and systemic manifestations. Data on this disease remain scarce. This study was undertaken to describe patient characteristics and disease evolution, identify prognostic factors, and define different clinical phenotypes of RP., Methods: We performed a retrospective study of 142 patients with RP who were seen between 2000 and 2012 in a single center., Results: Of the 142 patients, 86 (61%) were women. The mean ± SD age at first symptoms was 43.5 ± 15 years. Patients had the following chondritis types: auricular (89%; n = 127), nasal (63%; n = 89), laryngeal (43%; n = 61), tracheobronchial (22%; n = 32), and/orcostochondritis (40%; n = 57). The main other manifestations were articular (69%; n = 98), ophthalmologic (56%; n = 80), audiovestibular (34%; n = 48), cardiac (27%; n = 38), and cutaneous (28%; n = 40). At a mean ± SD followup of 13 ± 9 years, the 5- and 10-year survival rates were 95 ± 2% and 91 ± 3%, respectively. Factors associated with death on multivariable analysis were male sex (P = 0.01), cardiac abnormalities (P = 0.03), and concomitant myelodysplastic syndrome (MDS) (P = 0.004) or another hematologic malignancy (P = 0.01). Cluster analysis revealed that separating patients into 3 groups was clinically relevant, thereby separating patients with associated MDS, those with tracheobronchial involvement, and those without the 2 features in terms of clinical characteristics, therapeutic management, and prognosis., Conclusion: This large series of patients with definite RP revealed an improvement in survival as compared with previous studies. Factors associated with death were male sex, cardiac involvement, and concomitant hematologic malignancy. We identified 3 distinct phenotypes., (© 2016, American College of Rheumatology.)

Objective: To examine the role of comorbidity and pain in the associations of hand osteoarthritis (OA) with self-reported and performance-based physical function in a general population of elderly persons., Methods: We studied data from 2,942 participants ages 65-85 years in the European Project on OSteoArthritis, a collaborative observational study of 6 European cohorts (from Germany, Italy, The Netherlands, Spain, Sweden, and the UK). Outcome measures included self-reported physical function of the hands measured by the AUStralian/CANadian Osteoarthritis Hand Index (AUSCAN) for hand OA physical function subscale and performance-based grip strength measured using a strain gauge dynamometer., Results: Comorbidity was not a confounder in the association of hand OA with self-reported and performance-based functional limitations, while the role of pain as a mediator was confirmed. Anxiety, depression, stroke, and osteoporosis were associated with AUSCAN scores reflecting more impairment. Depression and osteoporosis were associated with less grip strength., Conclusion: Although comorbidity was decidedly and independently associated with hand functional limitation, it had no effect on the relationship of hand OA with physical function. Hand OA was found to be associated with both self-reported and performance-based physical function impairment; the association was found to be partially mediated by pain, which reduced its impact., (© 2016, American College of Rheumatology.)

Objective: Mevalonate kinase deficiency (MKD) is a rare metabolic disease characterized by recurrent inflammatory episodes. This study was undertaken to describe the genotype, phenotype, and response to treatment in an international cohort of MKD patients., Methods: All MKD cases were extracted from the Eurofever registry (Executive Agency for Health and Consumers project no. 2007332), an international, multicenter registry that retrospectively collects data on children and adults with autoinflammatory diseases., Results: The study included 114 MKD patients. The median age at onset was 0.5 years. Patients had on average 12 episodes per year. Most patients had gastrointestinal symptoms (n = 112), mucocutaneous involvement (n = 99), lymphadenopathy (n = 102), or musculoskeletal symptoms (n = 89). Neurologic symptoms included headache (n = 43), cerebellar syndrome (n = 2), and mental retardation (n = 4). AA amyloidosis was noted in 5 patients, almost twice as many as expected from findings in previous cohorts. Macrophage activation syndrome occurred in 1 patient. Patients were generally well between attacks, but 10-20% of the patients had constitutional symptoms, such as fatigue, between fever episodes. Patients with p.V377I/p.I268T compound heterozygosity had AA amyloidosis significantly more often. Patients without a p.V377I mutation more often had severe musculoskeletal involvement. Treatment with nonsteroidal antiinflammatory drugs relieved symptoms. Steroids given during attacks, anakinra, and etanercept appeared to improve symptoms and could induce complete remission in patients with MKD., Conclusion: We describe the clinical and genetic characteristics of 114 MKD patients, which is the largest cohort studied so far. The clinical manifestations confirm earlier reports. However, the prevalence of AA amyloidosis is far higher than expected., (© 2016, American College of Rheumatology.)

Objective: To elucidate the clinical and genetic features of patients with TNFRSF1A variants in Japan using data obtained from a nationwide survey conducted by the Ministry of Health, Labor, and Welfare of Japan study group for tumor necrosis factor receptor-associated periodic syndrome (TRAPS)., Methods: Inquiries were sent to 2,900 departments of internal medicine and pediatrics in all hospitals with more than 200 beds in Japan, asking whether they had patients in whom TRAPS was suspected. Genetic tests for TNFRSF1A, MEFV, and MVK were performed on 169 patients. Cell surface expression of TNFRSF1A variants was assessed using 293T cells., Results: Ten patients from 10 independent families were found to have TNFRSF1A variants. We collected clinical and genetic information on 41 additional patients with TNFRSF1A variants and symptoms of inflammation from 23 independent families; 17 of these patients had not been described in the literature. The common clinical features of Japanese patients were fever of >38°C (100% of patients), arthralgia (59%), and rash (55%). The prevalence of abdominal pain (36%), myalgia (43%), and amyloidosis (0%) was significantly lower in Japanese patients than in Caucasian patients. The most common variant was T61I (appearing in 49% of patients), and it was identified in 7 of 363 healthy controls. Defects in cysteine residues and the T50M variant were associated with decreased cell surface expression, while other variants, including T61I, were not., Conclusion: Patients with TNFRSF1A variants are very rare in Japan, as in other countries, but there are a number of clinical and genetic differences between Japanese and Caucasian patients. The pathogenic significance of the T61I variant remains unclear., (© 2016, American College of Rheumatology.)

Objective: To determine the association between changes in semiquantitative magnetic resonance imaging (MRI) biomarkers over 24 months and radiographic and pain progression over 48 months in knees with mild-to-moderate osteoarthritis (OA)., Methods: We undertook a nested case-control study as part of the Foundation for the National Institutes of Health Biomarkers Consortium Project. We used multivariable logistic regression models to examine the association between change over 24 months in semiquantitative MRI markers and radiographic and pain progression in knee OA. MRIs were read according to the MRI OA Knee Score system. We focused on changes in cartilage, osteophytes, meniscus, bone marrow lesions, Hoffa-synovitis, and effusion-synovitis., Results: The most parsimonious model included changes in cartilage thickness and surface area, effusion-synovitis, Hoffa-synovitis, and meniscal morphology (C statistic 0.740). Compared with no worsening, worsening in cartilage thickness in ≥3 subregions was associated with 2.8-fold (95% confidence interval [95% CI] 1.3-5.9) greater odds of being a case, and worsening in cartilage surface area in ≥3 subregions was associated with 2.4-fold (95% CI 1.3-4.4) greater odds of being a case. Worsening of meniscal morphology in any region was associated with 2.2-fold (95% CI 1.3-3.8) greater odds of being a case. Worsening effusion-synovitis and Hoffa-synovitis were also associated with a greater odds of being a case (odds ratios 2.7 and 2.0, respectively)., Conclusion: Twenty-four-month changes in cartilage thickness, cartilage surface area, effusion-synovitis, Hoffa-synovitis, and meniscal morphology were independently associated with OA progression, suggesting that these factors may serve as efficacy biomarkers in clinical trials of disease-modifying interventions for knee OA., (© 2016, American College of Rheumatology.)

Objective: To determine whether thigh muscle strength predicts the risk of undergoing knee replacement surgery, independent of radiographic severity of osteoarthritis and pain., Methods: Participants in the Osteoarthritis Initiative study who had received a knee replacement between the 12-month and 60-month follow-up visits (cases) were each matched with 1 control subject (who did not receive a knee replacement over 60 months) for age, sex, height, body mass index, baseline radiographic stage, and location of joint space narrowing. Isometric knee extensor and flexor strength was recorded biennially. The strength examination prior to knee replacement (≤2 years) was termed time 0, that 2 years prior to time 0 was termed time -2, and that 4 years prior to time 0 was termed time -4. Muscle strength in patients and controls was compared using paired t-tests and conditional logistic regression analysis adjusted for pain., Results: One hundred thirty-six participants (60% women, mean ± SD age 65 ± 9 years, body mass index 29 ± 4 kg/m(2) ) received a knee replacement during follow-up, had strength data for at least time 0, and had a matched control. Knee extensor strength at time 0 (primary outcome measure) was significantly lower in female patients compared with controls (P < 0.001, pain-adjusted odds ratio [ORadj ] 1.72, 95% confidence interval 1.16-2.56), but no significant difference was observed in men. Results were similar for knee flexor strength at time 0 and for longitudinal change in extensor and flexor strength between time -2 and time 0. Thigh muscle strength at time -2 or time -4, or change between time -4 and time -2, did not predict the risk of undergoing knee replacement surgery in men or women., Conclusion: Thigh muscle strength predicted the risk of undergoing knee replacement surgery in women, but not in men. The results of this study may identify a window during which the risk of undergoing knee replacement surgery in women can be modified., (© 2016, American College of Rheumatology.)

Objective: To determine the type and frequency of musculoskeletal symptoms at onset and during followup of cryopyrin-associated periodic syndromes (CAPS)., Methods: We retrospectively recorded the articular and muscular symptoms of patients with CAPS followed up in French hospitals. Data were presented as frequencies or the median (range), and patient groups were compared using chi-square test, Fisher's exact test, and Mann-Whitney test., Results: The study included 133 patients (33 children), 20 with familial cold autoinflammatory syndrome, 88 with Muckle-Wells syndrome, 22 with chronic infantile neurologic, cutaneous, articular syndrome, and 3 with unclassified CAPS. The median age was 35 years (range 0-78 years) at the time of the study, 1 year (range 0-41 years) at symptom onset, and 23 years (range 0-58 years) at diagnosis. The disease was sporadic in 17% of the patients. Cutaneous symptoms predominated at onset (77%), followed by articular symptoms (30%). The p.Thr348Met and p.Arg260Trp NLRP3 mutations were significantly associated with the presence and absence of articular symptoms at onset, respectively. During followup, 86% of the patients had musculoskeletal symptoms, 88% had arthralgia, and 58% had arthritis, but only 9% had joint destruction. Tendinopathies occurred in 21.5% of the patients, tender points in 16.5%, and myalgia in 33%. Only 3 patients had typical knee deformities. Radiographs were rarely obtained. Except for bone deformities, osteoarticular symptoms occurred at similar frequencies in the different CAPS phenotypes., Conclusion: Joint manifestations were frequent in all CAPS phenotypes. Bone deformities were rare. Musculoskeletal manifestations varied within given families but tended to worsen over time., (© 2015, American College of Rheumatology.)

Objective: To assess the association between pain mechanisms (sensitization) and biochemical markers for cartilage, bone, and inflammation in patients with knee pain., Methods: The study group comprised 281 patients with different degrees of knee pain intensity and radiographic findings (using the Kellgren/Lawrence [K/L] scale). The following structurally related serologic biomarkers were measured in serum: high-sensitivity C-reactive protein (hsCRP), matrix metalloproteinase (MMP)-mediated breakdown of CRP (CRPM), MMP-mediated degradation of type I collagen (C1M), C2M, and C3M. Pressure-pain thresholds (PPT) (peripheral and spreading sensitization), temporal summation of pain, and conditioning pain modulation (CPM) (with the latter 2 biomarkers representing generalized sensitization) were assessed. For each pain parameter, the patients were categorized as most sensitized or least sensitized., Results: Correlations were observed between the pain biomarkers PPT, temporal summation, and CPM and maximal pain intensity during the last 24 hours. Significant associations between most of the serologic biomarkers were observed. A high CRPM level was associated with centralized sensitization (temporal summation and CPM). None of the serologic markers correlated with the intensity or duration of knee pain, and only hsCRP correlated with the K/L grade. The most-sensitized group contained more women than men, and the least-sensitized group contained more men than women., Conclusion: A platform of mechanistic pain biomarkers in combination with structure-related serologic biomarkers provides new possibilities for understanding how osteoarthritis-related structural features may be associated with pain and pain sensitization. This study showed significant correlations between central pain sensitization and CRPM as a possible measure for chronic inflammation. Future pain association studies should include biomarkers representing the local joint environment more specifically., (Copyright © 2014 by the American College of Rheumatology.)

Objective: Exertional leg pain is a characteristic musculoskeletal manifestation of familial Mediterranean fever (FMF). We aimed to define the frequency and characteristics of exertional leg pain in a large cohort of FMF patients and to evaluate for additional signs and symptoms of spondyloarthritis (SpA) in this patient population., Methods: FMF patients were allocated into study or control groups based on the presence or absence of exertional leg pain. Randomly selected patients underwent magnetic resonance imaging (MRI) of the ankle as well as plain radiography of the sacroiliac joints., Results: The prevalence of exertional leg pain among the 170 FMF patients included in the study was 58.2%. Patients with exertional leg pain had significantly more joint attacks (74.7% versus 40.8%; P < 0.0001), fever attacks (35.4% versus 15.5%; P = 0.004), and pleuritis attacks (48.5% versus 29.6%; P = 0.013) as well as more attacks per year. Elevations of inflammation markers were significantly more frequent among the study group (for the erythrocyte sedimentation rate, 44.4% of patients versus 21.1% of patients; P = 0.016) (for the C-reactive protein level, 48.4% of patients versus 31.8% of patients; P = 0.013), and M694V homozygosity was more prevalent among the study group (45.5% versus 21.1%; P = 0.001). Signs compatible with enthesopathy on MRI were observed in 73.5% of patients in the study group and in 33.3% of patients in the control group (P = 0.046). Definite SpA was diagnosed in 41.2% of the patients in the study group compared to none of the controls (P = 0.07) (odds ratio 1.7 [95% confidence interval 1.2-2.3])., Conclusion: Exertional leg pain is a common manifestation of FMF and is a marker of a more severe disease phenotype. Additionally, exertional leg pain is frequently associated with sacroiliitis and an underlying ankle enthesopathy and should therefore be considered a new feature of SpA., (Copyright © 2014 by the American College of Rheumatology.)

Hyperexcitability of the central nervous system (CNS) has been suggested to play an important role in the chronic pain experienced by osteoarthritis (OA) patients. A systematic review following PRISMA guidelines was performed to evaluate the existing evidence from the literature related to the presence of central sensitization (CS) in patients with OA.Electronic databases PubMed and Web of Science were searched to identify relevant articles using pre-defined keywords regarding CS and OA. Full-text clinical reports addressing studies of CS in human adults with chronic complaints due to osteoarthritis were included and screened for methodological quality by two independent reviewers. From the 40 articles that were initially eligible for methodological quality assessment, 36 articles achieved sufficient scores and therefore were discussed. The majority of these studies were case-control studies and addressed OA of the knee joint. Different subjective and objective parameters considered manifestations of CS, which have been previously reported in other chronic pain conditions such as whiplash or rheumatoid arthritis, were established in subjects with OA pain. Overall results suggest that, although peripheral mechanisms are involved in OA pain, hypersensitivity of the CNS plays a significant role in a subgroup of subjects within this population. Although the majority of the literature provides evidence for the presence of CS in chronic OA pain, clinical identification and treatment of CS in OA is still in its infancy, and future studies with good methodological quality are necessary., (© 2014 European Pain Federation - EFIC®)

We studied the effects of intra-articularly injected bone marrow derived mesenchymal stem cells (MSCs), as well as freshly isolated bone marrow mononuclear cells (BMMNCs), on pain, cartilage damage, bone changes and inflammation in an in-vivo rat osteoarthritis (OA) model. OA was induced unilaterally by injection of mono-iodoacetate (MIA) and allowed to develop for 3 weeks. Then, animals were treated by intra-articular injection with MSCs, BMMNCs, or saline as a control. Four weeks later, pain was assessed with an incapitance tester, subchondral bone alterations were measured with µCT and cartilage quality and joint inflammation were assessed by histological analysis. Animals treated with MSCs distributed significantly more weight to the affected limb after treatment, which was not observed in the other groups. No statistically significant differences between treatment groups regarding cartilage damage, subchondral bone alterations and synovial inflammation were observed. Additional cell tracking experiments indicated adequate intra-articular cell injection and cell survival up to 2 weeks. In our OA model, injected MSCs were able to reduce MIA induced pain, as measured by an increased weight distribution to the affected limb. No statistically significant effects of the cellular therapies on structural damage and synovial inflammation were found., (© 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

Studies of lateral wedge insoles (LWIs) in medial knee osteoarthritis (OA) have shown reductions in the average external knee adduction moment (EKAM) but no lessening of knee pain. Some treated patients actually experience increases in the EKAM which could explain the overall absence of pain response. We examined whether, in patients with painful medial OA, reductions in the EKAM were associated with lessening of knee pain. Each patient underwent gait analysis whilst walking in a control shoe and two LWI's. We evaluated the relationship between change in EKAM and change in knee pain using Spearman Rank Correlation coefficients and tested whether dichotomizing patients into biomechanical responders (decreased EKAM) and non-responders (increased EKAM) would identify those with reductions in knee pain. In 70 patients studied, the EKAM was reduced in both LWIs versus control shoe (-5.21% and -6.29% for typical and supported wedges, respectively). The change in EKAM using LWIs was not significantly associated with the direction of knee pain change. Further, 54% were biomechanical responders, but these persons did not have more knee pain reduction than non-responders. Whilst LWIs reduce EKAM, there is no clearcut relationship between change in medial load when wearing LWIs and corresponding change in knee pain., (© 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

Objective: Osteoarthritis (OA) is a common chronic disease for which disease-modifying therapies are not currently available. Studies to seek new targets for slowing the progress of OA rely on mouse models, but these do not allow for longitudinal monitoring of disease development. This study was undertaken to determine whether gait can be used to measure disease severity in the STR/Ort mouse model of spontaneous OA and whether gait changes are related to OA joint pain., Methods: Gait was monitored using a treadmill-based video system. Correlations between OA severity and gait at 3 treadmill speeds were assessed in STR/Ort mice. Gait and pain behaviors of STR/Ort mice and control CBA mice were analyzed longitudinally, with monthly assessments., Results: The best speed to identify paw area changes associated with OA severity in STR/Ort mice was found to be 17 cm · seconds(-1) . Paw area was modified with age in CBA and STR/Ort mice, but this began earlier in STR/Ort mice and correlated with the onset of OA at 20 weeks of age. In addition, task noncompliance appeared at 20 weeks. Surprisingly, STR/Ort mice did not show any signs of pain with OA development, even when treated with the opioid antagonist naloxone, but did exhibit normal pain behaviors in response to complete Freund's adjuvant-induced arthritis., Conclusion: The present results identify an animal model in which OA severity and OA pain can be studied in isolation from one another. The findings suggest that paw area and treadmill noncompliance may be useful tools to longitudinally monitor nonpainful OA development in STR/Ort mice. This will help in providing a noninvasive means of assessing new therapies to slow the progression of OA., (© 2014 The Authors. Arthritis & Rheumatology is published by Wiley Periodicals, Inc. on behalf of the American College of Rheumatology.)

Objective: Knee osteoarthritis (OA) contributes significantly to disability in older individuals, and racial/ethnic minorities are disproportionately affected. The present study aimed to characterize differences in clinical and experimental pain, including pain inhibition, among older African American (AA) and non-Hispanic white (NHW) subjects with knee OA., Methods: AA and NHW subjects with knee OA (n = 267) completed clinical and functional pain assessments, including quantitative sensory testing (QST). We hypothesized that, when compared to NHW subjects, AA subjects would display 1) lower pain tolerance and higher ratings of heat-, mechanical-, and cold-induced pain, 2) greater temporal summation of pain, 3) reduced pain inhibition, and 4) greater clinical pain and poorer function. In addition, we hypothesized that the findings from QST would significantly predict the severity of clinical pain within each race/ethnicity., Results: AA subjects with knee OA displayed increased pain sensitivity, greater temporal summation, and reduced pain inhibition when compared to NHW subjects with knee OA. Moreover, AA subjects reported greater clinical pain and poorer function. Racial/ethnic differences in clinical pain became nonsignificant when the analyses were controlled for education and annual income, whereas differences in QST findings remained highly significant. Although the extent of pain inhibition predicted the severity of clinical pain in both groups, different QST measures were additionally predictive of clinical pain within each group., Conclusion: The results of this study establish that there are racial/ethnic differences in experimental and clinical pain and function in older individuals with knee OA. Our findings indicating that different QST measures were associated with clinical pain within the 2 racial/ethnic groups, whereas reduced pain inhibition was important in all participants, warrant further study in order to elucidate the common and group-specific pathophysiologic mechanisms contributing to clinical pain in OA., (Copyright © 2014 by the American College of Rheumatology.)

Gait measures are receiving increased attention in the evaluation of patients with knee osteoarthritis (OA). Yet, there remains a need to assess variability of gait analysis in patients with knee osteoarthritis over time and how pain affects variation in these gait parameters. The purpose of this study was to determine if important gait parameters, such as the knee adduction moment, knee flexion moment, peak vertical ground reaction force, and speed, were repeatable in patients with mild-to-moderate knee OA over a trial period of 12 weeks. Six patients were enrolled in this cross-over study design after meeting strict inclusion criteria. Gait tests were conducted three times at 4 week intervals and once after the placebo arm of a randomized treatment sequence; each gait test followed a 2-week period of receiving a placebo for a pain modifying drug. Repeatability for each gait variable was found using intraclass correlation coefficients (ICC) with a two-way random model. This study found that the knee adduction moment was repeatable throughout the four gait tests. However, normalized peak vertical ground reaction force and knee flexion moment were not as repeatable, varying with pain. This suggests that these gait outcomes could offer a more objective way to measure a patient's level of pain., (Copyright © 2012 Orthopaedic Research Society.)

Background: Interventions based on coping and acceptance can be adapted for people with different painful conditions. Evidence about baseline characteristics that predict improved outcomes is informative for matching people to interventions, whereas evidence about changes that predict improved outcomes is informative about the processes that interventions should target., Methods: Participants in a low-intensity programme to promote self-management of haemophilia-related chronic joint pain (n = 101) reported pain intensity, coping, acceptance and quality of life at baseline and 6-month follow-up. Baseline and change measures of pain intensity, coping and acceptance were used to predict follow-up quality of life, taking account of baseline quality of life., Results: Changed (reduced) pain intensity predicted better physical quality of life, independently of age, haemophilia severity, baseline pain intensity and baseline physical quality of life. Lower baseline passive coping and changed (increased) pain acceptance predicted better mental quality of life, independently of age, severity and baseline mental quality of life. Increased activity engagement but not pain willingness predicted better mental quality of life when pain acceptance was decomposed. Changed (reduced) negative thoughts also predicted better mental quality of life when separate acceptance subscales were used. Active pain coping did not predict physical or mental quality of life., Conclusions: Initially high levels of passive coping may be an obstacle to improving mental quality of life. Acceptance rather than coping may be a more useful behavioural change target, but more research is needed about the meanings and therapeutic implications of different elements of pain acceptance., (© 2012 European Federation of International Association for the Study of Pain Chapters.)

This study examined the influence of a 6-week gait retraining program on the knee adduction moment (KAM) and knee pain and function. Ten subjects with medial compartment knee osteoarthritis and self-reported knee pain participated in weekly gait retraining sessions over 6 weeks. Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores and a 10-point visual-analog pain scale score were measured at baseline, post-training (end of 6 weeks), and 1 month after training ended. Gait retraining reduced the first peak KAM by 20% (p < 0.01) post-training as a result of a 7° decrease in foot progression angle (i.e., increased internal foot rotation), compared to baseline (p < 0.01). WOMAC pain and function scores were improved at post-training by 29% and 32%, respectively (p < 0.05) and visual-analog pain scale scores improved by two points (p < 0.05). Changes in WOMAC pain and function were approximately 75% larger than the expected placebo effect (p < 0.05). Changes in KAM, foot progression angle, WOMAC pain and function, and visual-analog pain score were retained 1 month after the end of the 6-week training period (p < 0.05). These results show that a 6-week gait retraining program can reduce the KAM and improve symptoms for individuals with medial compartment knee osteoarthritis and knee pain., (Copyright © 2013 Orthopaedic Research Society.)

Objective: To evaluate the construct validity of a new rating scale for self-reported impairments in persons with late effects of polio., Design: Psychometric analysis of data on self-perceived impairments in persons with prior polio., Participants: Two hundred seventy-three persons with prior polio (119 men and 154 women; mean age, 63.5 years)., Method: Rasch analysis of a 13-item rating scale with 5 response categories, in which the participants rated how much they have been bothered by various post-polio-related impairments during the past 2 weeks., Results: The initial analysis showed disordered categories, misfit with some of the items, multidimensionality, and local dependency. After adjustment of the categories, which resulted in a 4-category rating scale, fit to the model was achieved, but the scale still showed signs of multidimensionality. Analyses of local dependency revealed correlations among some of the items, which resulted in a 5 testlet solution, which gave fit to the model and unidimensionality., Conclusion: After adjustment of the categories and local dependency, this new rating scale, Self-Reported Impairments in Persons With Late Effects of Polio, can be considered as unidimensional. The good psychometric properties implies that the Self-Reported Impairments in Persons With Late Effects of Polio scale could be a useful rating scale that would increase our understanding of the impairments that persons with late effects of polio can experience. With further refinements, this scale may assist in the planning and evaluation of appropriate rehabilitation interventions., (Copyright © 2013 American Academy of Physical Medicine and Rehabilitation. Published by Elsevier Inc. All rights reserved.)

The purpose of this study is to determine if patellar maltracking is more prevalent among patellofemoral (PF) pain subjects with patella alta compared to subjects with normal patella height. We imaged 37 PF pain and 15 pain free subjects in an open-configuration magnetic resonance imaging scanner while they stood in a weightbearing posture. We measured patella height using the Caton-Deschamps, Blackburne-Peel, Insall-Salvati, Modified Insall-Salvati, and Patellotrochlear indices, and classified the subjects into patella alta and normal patella height groups. We measured patella tilt and bisect offset from oblique-axial plane images, and classified the subjects into maltracking and normal tracking groups. Patellar maltracking was more prevalent among PF pain subjects with patella alta compared to PF pain subjects with normal patella height (two-tailed Fisher's exact test, p<0.050). Using the Caton-Deschamps index, 67% (8/12) of PF pain subjects with patella alta were maltrackers, whereas only 16% (4/25) of PF pain subjects with normal patella height were maltrackers. Patellofemoral pain subjects classified as maltrackers displayed a greater patella height compared to the pain free and PF pain subjects classified as normal trackers (two-tailed unpaired t-tests with Bonferroni correction, p<0.017). This study adds to our understanding of PF pain in two ways-(1) we demonstrate that patellar maltracking is more prevalent in PF pain subjects with patella alta compared to subjects with normal patella height; and (2) we show greater patella height in PF pain subjects compared to pain free subjects using four indices commonly used in clinics., (Copyright © 2012 Orthopaedic Research Society.)

Patellofemoral pain syndrome causes significant discomfort and disability among much of the general population. Despite recent breakthroughs in dynamic three-dimensional imaging technologies to assess pathological patellofemoral motion, such tools remain costly for clinical diagnostics applications. Thus, this study investigated whether three-dimensional patellofemoral kinematics could be predicted from routine two-dimensional static measures of patellofemoral joint alignment quantified from magnetic resonance imaging (MRI) data acquired in full knee extension. Twenty-six volunteers clinically diagnosed with patellofemoral pain (19 F/7 M, 25.9 ± 11.1 years) and 26 control subjects (19 F/7 M, 25.3 ± 7.7 years) were included in this IRB-approved study. Static three-dimensional sagittal T1-weighted gradient recall echo and dynamic MRI scans were acquired. For the dynamic image acquisition, subjects cyclically flexed and extended their knee (at 30 cycles/min) while a full cine-phase contrast MRI set (24 time frames of anatomic images and x-, y-, and z-velocity images) was acquired. From these data, static measures of patellofemoral alignment and three-dimensional patellofemoral kinematics were derived. Single and multiple regressions between static and kinematic variables were evaluated. Although shown reliable, the static MRI measures could only partially predict patellofemoral kinematics, with r(2) -values ranging from 16% to 77%. This makes it imperitave that the current precise, accurate, 3D, dynamic imaging techniques be translated into clinical tools., (Copyright © 2012 Orthopaedic Research Society.)

Objective: To estimate the prognostic value of pain in one body region on the risk for developing chronic pain in other body regions., Methods: Prospective cohort study among 5052 Danish female health care workers responding to a baseline and follow-up questionnaire in 2005 and 2006, respectively. Using adjusted logistic regression analysis, the risk for developing chronic pain (>30 days last year) at follow-up in the low back (among those without low back pain during the last year at baseline) when experiencing sub-chronic (1-30 days last year) or chronic pain in other body regions (i.e., the neck/shoulders and/or the knees at baseline) was modelled. Similar risks were modelled for developing chronic pain in the neck/shoulders and knees., Results: Chronic pain in the neck/shoulders (OR 3.14; 95% CI 1.74-5.70) or knees (OR 2.57; 95% CI 1.28-5.16) at baseline increased the risk for developing chronic pain in the low back at follow-up. Likewise, chronic pain in the neck/shoulders (OR 2.39; 95% CI 1.36-4.17) or low back (OR 1.82 95%; CI 1.07-3.09) at baseline increased the risk for developing chronic pain in the knees at follow-up. The risk for developing chronic neck/shoulder pain was not significantly increased when having pain in the low back or knees at baseline., Conclusion: Among health care workers, chronic musculoskeletal pain in one body region increases the risk for developing chronic pain in other pain-free body regions. Prevention of musculoskeletal disorders among health care workers should focus holistically on the musculoskeletal system., (© 2012 European Federation of International Association for the Study of Pain Chapters.)

The study aim was to address the need for objective markers of pain-modifying interventions by testing the hypothesis that selective gait measures of knee joint loading can distinguish differences between non-steroidal anti-inflammatory (NSAID), analgesic treatment (opioid-receptor agonist), and placebo in patients medial knee osteoarthritis (OA). A randomized, single-blind washout, double-blind treatment, double-dummy cross-over trial using three treatment arms placebo, opioid (Oxycodone), and NSAID (Celecoxib) in medial compartment knee OA patients. Six patients with Kellgren-Lawrence radiographic severity grades of 2 or 3 completed six testing sessions (gait and pain assessment) at 2-week intervals. A significant increase was found in the knee total reaction moment and vertical ground reaction force (GRF) for Celecoxib compared to placebo (p=0.005, p=0.003), but not for Oxycodone compared to placebo (p=0.20, p=0.27) treatments. Walking speed was significantly higher for the Celecoxib and Oxycodone compared to placebo treatment (p=0.041 and p=0.031, respectively). Self-reported function (WOMAC scores) was not different among treatments (p>0.05). The changes in total reaction moments and GRFs for only the NSAID suggest that greater increases in joint loading occurs when joint inflammation is treated in addition to pain. The total knee reaction moment, representing the magnitude of the extrinsic moment, appears to be a sensitive marker, more so than self-reported metrics, for evaluating knee OA treatment effects., (Copyright © 2011 Orthopaedic Research Society.)

Musculoskeletal health can be compromised by breast cancer treatment. In particular, bone loss and arthralgias are prevalent side effects experienced by women treated with chemotherapy and/or adjuvant endocrine therapy. Bone loss leads to osteoporosis and related fractures, while arthralgias threaten quality of life and compliance to treatment. Because the processes that lead to these musculoskeletal problems are initiated when treatment begins, early identification of women who may be at higher risk of developing problems, routine monitoring of bone density and pain at certain stages of treatment, and prudent application of therapeutic interventions are key to preventing and/or minimizing musculoskeletal sequelae. Exercise may be a particularly suitable intervention strategy because of its potential to address a number of impairments; it may slow bone loss, appears to reduce joint pain in noncancer conditions, and improves other breast cancer outcomes. Research efforts continue in the areas of etiology, measurement, and treatment of bone loss and arthralgias. The purpose of this review is to provide an overview of the current knowledge on the management and treatment of bone loss and arthralgias in breast cancer survivors and to present a framework for rehabilitation care to preserve musculoskeletal health in women treated for breast cancer., (Copyright © 2012 American Cancer Society.)

This study investigated the load-modifying and clinical efficacy of variable-stiffness shoes after 12 months in subjects with medial compartment knee osteoarthritis. Subjects who completed a prior 6-month study were asked to wear their assigned constant-stiffness control or variable-stiffness intervention shoes during the remainder of the study. Changes in peak knee adduction moment, total Western Ontario and McMaster Universities (WOMAC), and WOMAC pain scores were assessed. Seventy-nine subjects were enrolled, and 55 completed the trial. Using an intention-to-treat analysis, the variable-stiffness shoes reduced the within-day peak knee adduction moment (-5.5%, p < 0.001) in the intervention subjects, while the constant-stiffness shoes increased the peak knee adduction moment in the control subjects (+3.1%, p = 0.015) at the 12-month visit. WOMAC pain and total scores for the intervention group were significantly reduced from baseline to 12 months (-32%, p = 0.002 and -35%, p = 0.007, respectively). The control group had a reduction of 27% in WOMAC pain score (p = 0.04) and no significant reduction in total WOMAC score. Reductions in WOMAC pain and total scores were similar between groups (p = 0.8 and p = 0.47, respectively). In the intervention group, reductions in adduction moment were related to improvements in pain and function (R(2)  = 0.11, p = 0.04). Analysis by disease severity revealed greater efficacy in adduction moment reduction in the less severe intervention group. While the long-term effects of the intervention shoes on pain and function did not differ from control, the data suggest wearing the intervention shoe reduces the within-day adduction moment after long-term wear, and thus should reduce loading on the affected medial compartment of the knee., (Copyright © 2011 Orthopaedic Research Society.)

Objective: To evaluate noninvasive monopolar capacitive-coupled radiofrequency (mcRF) for the treatment of pain associated with lateral elbow tendinopathies., Design: Prospective, single-center, single-arm, 1-year follow-up., Setting: Private sports medicine practice., Participants: Thirty-nine consecutive patients with diagnosis of lateral elbow tendinopathy (including 3 bilateral cases, for a total of 42 elbows) participated in the study. All patients had been unsuccessfully treated with a variety of nonoperative therapies (eg, nonsteroidal anti-inflammatory drugs, corticosteroid injections, and braces) for at least 3 months before they were enrolled in the study., Intervention: Patients were treated with mcRF technology in the office without local anesthetic or any particular preparation. Anatomic landmarks and careful determination of the most tender point defined the area treated; rapid and precise mcRF pulses were delivered covering the area in a staggered fashion; and 10 additional pulses were delivered directly to the point of maximum tenderness (total of 100 pulses). Patients returned to activities of daily living without restriction and were instructed to avoid nonsteroidal anti-inflammatory drugs and/or ice over the treated area. Physical therapy or other treatment modalities were disallowed., Results: The presence of pain before enrollment ranged from 15 weeks to 2 years (average, 32 weeks). Visual analog scores at rest, with regular activity, and with triggering events were gathered at 3, 6, and 12 months. The Nirschl Tennis Elbow Questionnaire and patient satisfaction also were used to evaluate study outcomes. Follow-up average was 423 days (range, 330-487 days). On the basis of the study's multifactorial success criteria, 81% of participants had successful outcomes. Furthermore, 89% of the patients who completed the study were completely or moderately satisfied with the outcome., Conclusions: Outcomes of this study suggest that noninvasive mcRF may have a role in the treatment of pain associated with lateral elbow tendinopathies. The noninvasive nature of the procedure and the safety and efficacy suggested by this study may offer significant advantages over current treatment alternatives. Further research in the form of a randomized clinical trial is recommended., (Copyright © 2012 American Academy of Physical Medicine and Rehabilitation. Published by Elsevier Inc. All rights reserved.)

Chronic pain is a hallmark of osteoarthritis (OA), yet little is known about its properties and representation in the brain. Here we use fMRI combined with psychophysics to study knee pain in fourteen OA patients and nine healthy controls. Mechanical painful pressure stimuli were applied to the knee in both groups and ratings of evoked pain and related brain activity examined. We observe that psychophysical properties and brain activation patterns of evoked pain are essentially the same between OA patients and healthy subjects, and between worse and better OA knees. In OA patients, stimulus-related brain activity could be distinguished from brain activity associated with spontaneous pain. The former activated brain regions commonly observed for acute painful stimuli in healthy subjects, while the spontaneous pain of OA engaged prefrontal-limbic regions closely corresponding to areas observed for spontaneous pain in other chronic pain conditions, such as chronic back pain and post-herpetic neuralgia. Arthritis-related clinical characteristics of knee OA also mapped to prefrontal-limbic regions. In a subgroup of patients (n=6) we examined brain activity changes for a 2-week, repeat measure, cyclooxygenase-2 inhibitor (valdecoxib) therapy. Treatment decreased spontaneous pain for the worse knee and clinical characteristics of OA, and increased blood and csf levels of the drug which correlated positively with prefrontal-limbic brain activity. These findings indicate dissociation between mechanically induced and spontaneous OA knee pain, the latter engaging brain regions involved in emotional assessment of the self, and challenge the standard clinical view regarding the nature of OA pain., (Copyright © 2011 European Federation of International Association for the Study of Pain Chapters. Published by Elsevier Ltd. All rights reserved.)

Background: Temporomandibular disorders (TMDs) are considered a collection of disorders involving many organic, psychological and psychosocial factors. They can involve the masticatory muscles or the temporomandibular joint (TMJ) and associated structures, or both. It is estimated that 40% to 75% of the population displays at least one sign of the disease and 33% of the population reports at least one symptom. Arthroscopy has been used to reduce signs and symptoms of patients with TMD but the effectiveness has still not been totally explained., Objectives: To assess the effectiveness of arthroscopy for the management of signs and symptoms in patients with TMDs., Search Strategy: The Cochrane Oral Health Group Trials Register (to 23 December 2010), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 4, 2010), MEDLINE via OVID (1950 to 23 December 2010), EMBASE via OVID (1980 to 23 December 2010), LILACS via BIREME Virtual Health Library (1982 to 23 December 2010), Allied and Complementary Medicine Database (AMED) via OVID (1985 to 23 December 2010), CINAHL via EBSCO (1980 to 23 December 2010). There were no restrictions regarding the language or date of publication., Selection Criteria: Randomized controlled clinical trials of arthroscopy for treating TMDs were included., Data Collection and Analysis: Two review authors independently extracted data, and three review authors independently assessed the risk of bias of included trials. The authors of the selected articles were contacted for additional information., Main Results: Seven randomized controlled trials (n = 349) met the inclusion criteria. All studies were either at high or unclear risk of bias. The outcome pain was evaluated after 6 months in two studies. No statistically significant differences were found between the arthroscopy versus nonsurgical groups (standardized mean difference (SMD) = 0.004; 95% confidence interval (CI) -0.46 to 0.55, P = 0.81). Two studies, analyzed pain 12 months after surgery (arthroscopy and arthrocentesis) in 81 patients. No statistically significant differences were found (mean difference (MD) = 0.10; 95% CI -1.46 to 1.66, P = 0.90). Three studies analyzed the same outcome in patients who had been submitted to arthroscopic surgery or to open surgery and a statistically significant difference was found after 12 months (SMD = 0.45; 95% CI 0.01 to 0.89, P = 0.05) in favor of open surgery. The two studies compared the maximum interincisal opening in six different clinical outcomes (interincisal opening over 35 mm; maximum protrusion over 5 mm; click; crepitation; tenderness on palpation in the TMJ and the jaw muscles 12 months after arthroscopy and open surgery). The outcome measures did not present statistically significant differences (odds ratio (OR) = 1.00; 95% CI 0.45 to 2.21, P = 1.00). Two studies compared the maximum interincisal opening after 12 months of postsurgical follow-up. A statistically significant difference in favor of the arthroscopy group was observed (MD = 5.28; 95% CI 3.46 to 7.10, P < 0.0001). The two studies compared the mandibular function after 12 months of follow-up with 40 patients evaluated. The outcome measure was mandibular functionality (MFIQ). This difference was not statistically significant (MD = 1.58; 95% CI -0.78 to 3.94, P = 0.19).  , Authors' Conclusions: Both arthroscopy and nonsurgical treatments reduced pain after 6 months. When compared with arthroscopy, open surgery was more effective at reducing pain after 12 months. Nevertheless, there were no differences in mandibular functionality or in other outcomes in clinical evaluations. Arthroscopy led to greater improvement in maximum interincisal opening after 12 months than arthrocentesis; however, there was no difference in pain.

Fibromyalgia syndrome (FS) frequently co-occurs with regional pain disorders. This study evaluated how these disorders contribute to FS, by assessing effects of local active vs placebo treatment of muscle/joint pain sources on FS symptoms. Female patients with (1) FS+myofascial pain syndromes from trigger points (n=68), or (2) FS+joint pain (n=56) underwent evaluation of myofascial/joint symptoms [number/intensity of pain episodes, pressure pain thresholds at trigger/joint site, paracetamol consumption] and FS symptoms [pain intensity, pressure pain thresholds at tender points, pressure and electrical pain thresholds in skin, subcutis and muscle in a non-painful site]. Patients of both protocols were randomly assigned to two groups [34 each for (1); 28 each for (2)] to receive active or placebo local TrP or joint treatment [injection/hydroelectrophoresis] on days 1 and 4. Evaluations were repeated on days 4 and 8. After therapy, in active--but not placebo-treated-- groups: number and intensity of myofascial/joint episodes and paracetamol consumption decreased and pressure thresholds at trigger/joint increased (p<0.001); FS pain intensity decreased and all thresholds increased progressively in tender points and the non-painful site (p<0.0001). At day 8, all placebo-treated patients requested active local therapy (days 8 and 11) vs only three patients under active treatment. At a 3-week follow-up, FS pain was still lower than basis in patients not undergoing further therapy and had decreased in those undergoing active therapy from day 8 (p<0.0001). Localized muscle/joint pains impact significantly on FS, probably through increased central sensitization by the peripheral input; their systematic identification and treatment are recommended in fibromyalgia., (Copyright © 2010 European Federation of International Association for the Study of Pain Chapters. Published by Elsevier Ltd. All rights reserved.)

This study tested the effects of variable-stiffness shoes on knee adduction moment, pain, and function in subjects with symptoms of medial compartment knee osteoarthritis over 6 months. Patients were randomly and blindly assigned to a variable-stiffness intervention or constant-stiffness control shoe. The Western Ontario and McMaster Universities (WOMAC) score served as the primary outcome measure. Joint loading, the secondary outcome measure, was assessed using the external knee adduction moment. Peak external knee adduction moment, total WOMAC, and WOMAC pain scores were assessed at baseline and after 6 months. The total WOMAC and WOMAC pain scores for the intervention group were reduced from baseline to 6 months (p = 0.017 and p = 0.002, respectively), with no significant reductions for the control group. There was no difference between groups in magnitude of the reduction in total WOMAC (p = 0.50) or WOMAC pain scores (p = 0.31). The proportion of patients achieving a clinically important improvement in pain was greater in the intervention group than in the control group (p = 0.012). The variable-stiffness shoes reduced the peak knee adduction moment (-6.6% vs. control, p < 0.001) in the 34 intervention subjects at 6 months. The adduction moment reduction significantly improved (p = 0.03) from the baseline reduction. The constant-stiffness control shoe increased the peak knee adduction moment (+6.3% vs. personal, p = 0.004) in the 26 control subjects at 6 months. The results of this study showed that wearing the variable-stiffness shoe lowered the adduction moment, reduced pain, and improved functionality after 6 months of wear. The lower adduction moment associated with wearing this shoe may slow the rate of progression of osteoarthritis after long-term use., ((c) 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)